The overall objectives of this proposal are to provide new information on (1) the development of deoxyribonucleoside analogs as new anticancer agents and (2) the logical use of combination chemotherapy in the therapy of neoplastic diseases. Initially, the properties of deoxyribonucleotide metabolizing enzymes in human tissues will be studied; enzymes such as ribonucleotide reductase, dUTP pyrophosphatase, N-glycosidase specific for uracil in DNA, dCMP deaminase and TMP kinase have so far not been well characterized and emphasis will be placed on evaluating the regulatory properties and the relationship between analog structure and enzyme activity. Previous experience in studying various human deoxyribonucleotide metabolizing enzymes will be used to develop methodology applicable to purification of these enzymes from a single source. Simultaneously, deoxyribonucleotide metabolism and regulation will be studied in order to gain knowledge useful in sensitizing or desensitizing human cells against deoxynucleoside analogs. Finally, the metabolism and mechanism of action of some active analogs will be examined with emphasis on two new promising antitumor analogs: 2'azido cytidine and ara-azido-cytidine.